3-(ethynyl/vinyl-3-hydroxy-3a-methyl-7-oxopolyhydrobenz[e]indanes and esters thereof



ited tates tent huh 3,tl ii,372. 3=(ETHYNYL/WNYlL S-HYDRGXY 3n METHYL- 7-9X0 ?OLYl'iYDR@BENZ{e]iNDANE AND ES- TERS THEREQF Leland J. Chhzn, Morton Grove, BL, assignor to G. D. earle & Co., Chicago, llh, a corporation of Delaware N Drawing. Filed Mar. 5, 1959, er. No. 7%),345 7 Claims. (6!. 263-488) This invention relates to 3-(ethynyl/vinyl)-3-hydroxy- 3a methyl 7 oxopolyhydrobenz[elindanes and esters thereof, as also to processes whereby these products can be manufactured. More particularly, this invention relates to compounds of the formula CO-lower al'kyl wherein the lower alkyl constituent is such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and like C H aggregates in which n represents a positive integer amounting to less than 9.

The products to which this invention relates are useful because of their valuable pharmacological properties. Thus, for example, they are diureticsfrom which it fol lows that the intermediates whence these products can be manufactured are likewise useful.

The following examples describe in detail certain of the compounds illustrative of the present invention, and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. In the examples hereinafter set forth, temperatures aregiven in degrees Centigrade and relative amounts of materials in parts by Weight, except as otherwise noted.

Example 1 troduced in small increments, whereupon the blue reaction mixture is let stand for 80 minutes and then cautiously diluted with 4 parts of methyl alcohol, agitation being continued throughout. The ammonia is then evapass sts solvent by evaporation. The residue, recrystallized from heptane, melts at 92.5-94". The colorless dense crystalline material thus obtained is 3-hydroxy-7-methoxy-3amethyl-321,4,5,6,9,9b-hexahydrobenz[e]indane, of the formula ona moo

(B) 7 methoxy 3a methyl 3 0x0 3a,4,5,6,9,9bhexahydrobenz[e]indaize.To a solution of 30 parts of cyclohexanone and 6 parts of 3-hydroxy-7-methoxy-3amethyl-3a,4,5,6,9,9b-hexahydrobenz[eJindane in 195 parts of dry toluene at the boiling point under reflux in a nitrogen atmosphere is added, with agitation during 5 minutes, a solution of 6 parts of aluminum isopropoxide in approximately 70 parts of dry toluene. Agitation at the boiling point under reflux is continued thereafter for 1 hour, at which point the resultant mixture is cooled and diluted with approximately 60 parts of a saturated aqueous solution of Rochelle salt. Excess cyclohexanone is then removed by steam distillation, following which the pale yellow solid precipitated in the distilland is collected on a filter, rinsed thereon with water, and dried in vacuo over sodium hydroxide. The 7-methoxy-3a-methyl-3-oxo-3a, 4,5,6,9,9b-hexahydrobenz[e]indane' thus obtained is crystallized from hexane, using decolorizing charcoal in process. The product comes out as dense white crystals melting at 9799. It has the formula (C) 3-ethynyl-3 hydroxy-7-methoxy-3a-methyl-3a,4,5, 6,9,9b-hexahydr0benz[e]indane.To a solution of 34 parts of potassium in 640 parts of anhydrous tert-butyl alcohol under nitrogen is added parts of dry toluene. The resultant mixture is cooled to roughly 0-5 and saturated thereat with acetylene, whereupon a solution of 34 parts of 7-methoxy-3a-methyl-3-oxo-3a,4,5,6,9,9b-hexahydrobenz[e]indane in- 180 parts of dry toluene is mixed in. A moderate stream of acetylene is then passed over the surface of the mixture at 0 for 6 hours, during which time vigorous agitation is'continuously' maintained.- The mixture is then diluted with water and thereupon extracted with ether. Removalof solvent from the ether extract by distillation leaves a residue which crystallizes from hexanef as a dense material melting at 112113. This material I Patented June 26, 1962- is the desired 3-ethynyl 3-hydroxy-7-methoxy-3a-methyl- 33.,4,5,6,9,9b-hexahydrobenz{e1indane, of the formula CECE moo

(D) 3-2thynyl-d hydroxy-3mmethyl-7-0x0-3a,4,5,6,7,8,

9,9b-ctahydrobenz[e1indane.A solution of approximately 6 parts of 3-ethynyl-3-hydroxy-7-methoxy-3 a-methyl-3a,4,5,6,9,9b-hexahydrobenz[e]indane and 3 parts of oxalic acid dihydrate in a mixture of 120 parts of methyl alcohol and 30 parts of water is let stand at room tempera; tures for 1 hour, whereupon 1 part of sodium carbonate monohydrate is introduced. The resultant mixture is extracted with ether, and the etherealextract in turn washed Example 3 3-acet0xy-3-ethynyl 3a methyl 7-0x0-3a,4,5,7,8,9,9a, 9b-0ctahydr0benz [e1indane.-A mixture of 11 parts of 3- ethynyl 3 hydroxy-3a-methyl-7-oxo-3a,4,5,7,8,9,9a,9boctahydrobenz[e]indane, 30 parts of pyridine, and 30 parts of acetic anhydride is maintained with agitation at 78 for 2.days.' The mixture is then poured into ice-water,

with successive portions of water and a saturated aqueous solution of sodium bicarbonate. The extract is then dried over anhydrous sodium sulfate and stripped of solvent by evaporation. The residue is the @q-unsaturated ketone, 3-ethynyl-3-hydroxy-3a-methyl 7 oxo3a,4,5,6,7,8,9,9boctahydrobenz [e]indane, of the formula CECE Example 2 3-ethynyl-3-hydroxy 3a methyl-7-0xa-3a,4,5,7,8,9,9a, 9b-octahydrob'enzlje]indane.--To approximately 27 parts of 3-ethynyl-3-hydroxy 'Z-methoxy-3a-methyl-3a,4,5,6,9, 9b-hexahydrobenz[e]indane is added 12 parts of concentrated hydrocholrlc acid, 10 parts of water and 120 parts of methyl alcohol. The resultant mixture is maintained at room temperatures with agitation for 3 hours in an at-' 9b-octahydrobenzie1indane, as colorless massive dense crystals melting at 188-1895". The product has the formula CECE is substituted for 3-ethynyl-3-hydroxy-7-methoxy-3a-rnethyl3a,4,5,6,9,9b-hexahydrobenz[e] indane in the foregoing procedure.

precipitating an oil which is induced to solidify on standing. The solid product is collected on a filter, washed thereon with Water, and recrystallized from a mixture of ether and pentane. There is obtained by this means as colorless rods, 3-acetoxy-3-ethynyl-3a-methyl-7-oxo-3a,4, 5,7,8,9,9a,9b-octahydrobenz[e]indane melting at 16'7 168.5. The product has the formula CECE Example 4 3 hydroxy 3a methyl 7 0x0 3 vinyl 3a,4,5,7,- 8,9,9a,9b-0ctahydr0benz[e]indane.--To a solution of 2 parts of 3-ethynyl- 3-hydroxy-3a-methyl17-oxo-3a,4,5,7,8,- 9,9a,9b-octahydrobenz[e]indane in a mixture of 100 parts of dioxane and 20 parts of pyridine is added 1 part of 5% palladium-on-calcium carbonate catalyst. The resultant mixture is reduced by agitation under hydrogen at atmospheric pressure. When the uptake of hydrogen indicates conversion of the ethynyl to a vinyl linkage (representatively, after /2 hour), the reduction is stopped and the catalyst removed by filtration. Solvent is stripped from the filtrate by vacuum distillation, leaving a viscous oil which is taken up in ether. The ether extract is washed with a 5% solution of hydrochloric acid, water, and saturated aqueous sodium chloride, in that order. The extract is then dried over anhydrous sodium sulfate and stripped of solvent by evaporation. The residue, crystallized from a mixture of ether and pentane, affords the desired 3-hydroxy 3a methyl 7 10x0 3 vinyl 3a,4,5,7,8,9,9a,- 9b-octahydrobenz[e]indane as colorless needles melting at 1025-1045 The product has the formula Example 5 3a 4 methyl 7 0x0 3 propionyloxy 3 vinyl 3a,4,- 5,7,8,9,9a,9b-ocmhydrob enz[e]indane.--A solution of 3 parts of 3-hydroxy-3a-methyl-7-oxo-3-vinyl-3a,4,5,7,8,9,- 9a,9b-octahydrobenz[e]indane in a mixture of 3 parts of p-toluene sulfonic acid monohydrate, 50 parts of propionic acid, and 50 parts of propionic anhydride is maintained at room temperatures for 16 hours in an atmosphere of nitrogen. The solution is then poured into a mixture of ice and watenprecipitating an oil which is extracted with ether. The ether extract is Washed successively with water, an aqueous 5% soltuion of sodium bicarbonate, water again, and a saturated aqueous solution of sodium chloride. It is then dried over anhydrous sodium sulfate and stripped of solvent by evaporation. The residue thus 5 obtained is 3a-methy1-7-oxo-3-propionyloxy-3-vinyl-321,4,- 5,7,8,9,9a,9b-octahydrobenz[e]indane, of the formula CH=CH2 joooomcm wherein X is selected from the group consisting of ethynyl and vinyl radicals, R is selected from the group consisting of hydrogen and lower alkanoyl radicals, and the dotted line represents a double bond in solely 1 of the positions 5a(6) and 5a(9a).

2. 3 ethynyl 3 hydroxy 3a methyl 7 0x0 3a,- 4,5,6,7,8,9,9b-octahydrobenz[e]indane.

3. 3 ethynyl 3 hydroxy 3a methyl 7 oxo 3a,- 4,5,7,8,9,9a,9b-octahydrobenz[e]indane.

4. 3 acetoxy 3 ethynyl 3a methyl 7 oxo 3a,4,- 5,7,8,9,9a,9b-octahydrobenz[e] indane.

5. 3 hydroxy 3a methyl 7 oxo 3 vinyl 3a,4,5,- 7,8,9,9a9b-octahydrobenz[e]indane.

6. 7 methoxy 3a methyl 3 0x0 3a,4,5,6,9,9bhexahydrobenz[e] indane.

7. 3 ethynyl 3 hydroxy 7 methoxy 3a methyl- 321,4,5,6,9,9b-hexahydrobenz[e]indane.

N 0 references cited. 

1. A COMPOUND OF THE FORMULA 